Abstract Thoracic aortic diseases, including aneurysm and dissection, are an area of major unmet medical need due to a paucity of knowledge on the underlying mechanisms. Our long-term interest in thoracic aortic diseases using mouse models has provided compelling evidence that (1) AngII-induced thoracic aortic diseases are characterized by luminal dilation and intralamellar hematoma in the ascending aorta, which are most pronounced in the outer medial layers, resembling observations in human ascending aortic aneurysm and dissection, (2) interaction between angiotensin II (AngII) and its receptor subtype, AT1a receptor, plays a crucial role in the development of thoracic aortic aneurysm and dissection, (3) deletion of AT1a receptors in fibroblasts, not in smooth muscle cells (SMCs), is responsible for the AngII- induced thoracic aortic pathologies, (4) SMC-specific deficiency of LRP1 (an important protein in maintaining vascular integrity) augments AngII-induced thoracic aortic diseases. Consistent with our findings, thoracic aortic pathologies in mice with genetic deletions (without other manipulations) in SMCs including LRP-1, TGF-?R2, and fibulin-4 have striking similarities to AngII-induced thoracic aortic diseases. The ascending aorta is a unique aortic region in which SMCs are derived from two distinct embryonic origins, the cardiac neural crest (CNC) and second heart field (SHF). On the basis of our own data and the literature evidence, we hypothesize that thoracic aortic aneurysm and dissection result from AngII stimulation of adventitial fibroblasts interacting with subpopulations of medial SMCs that form an outer ?sleeve? in disease-prone areas. Two aims are proposed to test this hypothesis. Aim 1 will determine whether fibroblast migration or plasticity is actuated by AT1a receptors and contributes to the pathological processes of thoracic aortic aneurysm and dissection. Aim 2 will determine whether SMCs from different embryonic origins have intrinsically different functions that contribute to thoracic aortic aneurysm and dissection. Lineage tracking and in vivo manipulations will be used for the experiments proposed in these two aims. Completion of the proposed aims will provide insights into understanding whether cellular communication between fibroblasts in the adventitia and SMCs in the media of the aorta plays a crucial role in the development of ascending aortic aneurysms and dissection, and whether region specific characterization of thoracic aortic diseases is attributed to the ?biparental? feature of the SMC origin in the ascending aorta.